Insights into the Relationship between Nucleolar Stress and the NF-κB Pathway

Abstract

The nuclear organelle the nucleolus and the transcription factor nuclear factor of κ-light-chain-enhancer of activated B cells (NF-κB) are both central to the control of cellular homeostasis, dysregulated in common diseases and implicated in the ageing process. Until recently, it was believed that they acted independently to regulate homeostasis in health and disease. However, there is an emerging body of evidence suggesting that nucleoli and NF-κB signalling converge at multiple levels. Here we will review current understanding of this crosstalk. We will discuss activation of the NF-κB pathway by nucleolar stress and induction of apoptosis by nucleolar sequestration of NF-κB/RelA. We will also discuss the role of TIF-IA, COMMD1, and nucleophosmin, which are key players in this crosstalk, and the therapeutic relevance, particularly with respect to the antitumour effects of aspirin. Nucleoli-NF-κB-Nucleoli: An Emerging Signalling Network There are many parallels between nucleoli and the nuclear factor of κ-light-chain-enhancer of activated B cells (NF-κB) transcription factor. For example, both are stimulated by the same plethora of stresses (Table 1), both regulate the same downstream physiological processes, both are dysregulated in a variety of common diseases which contributes to disease aetiology, and both are implicated in senescence and ageing [1-6]. Until recently, it was believed that these factors act independently to regulate cellular homeostasis in health, ageing, and disease. However, there is a growing body of evidence to suggest that nucleolar stress activates the NF-κB pathway, and that nucleolar sequestration of NF-κB components is a critical apoptotic regulator. Here we will review the various levels of convergence between NF-κB and the nucleolus. We will also discuss the relevance of nucleoli-NF-κB crosstalk to the antitumour mechanisms of aspirin and the potential relevance to senescence and ageing. Highlights Nucleoli play a critical role in maintaining cellular homeostasis in health, ageing, and disease, as does the NF-κB transcription factor pathway. Emerging data suggest that interplay between these two cellular factors regulates cell growth and death. An atypical nucleolar stress response pathway, characterized by degradation of the PolI complex component, TIF-IA, and nucleolar enlargement, lies upstream of NF-κB pathway activation. Components of the NF-κB complex accumulate in nucleoli in response to stress. The presence of RelA in nucleoli triggers cytoplasmic relocation of nucleophosmin which mediates apoptosis by transporting BAX to mitochondria.

Post-translational Modifications of IκBα: The State of the Art

“…First, considering the unavoidable adverse effects of the IκBα-related NF-κB inhibitors ( Pancheri et al, 2020 ), the pathophysiological mechanisms and the significance of the IκBα–NF-κB pathway in the development of diseases should be further clarified to provide the best ratio of benefit to risk. Second, the drug release controllability to ensure the controllable release rate under certain specific pathophysiological conditions should be taken into account because of the vast regulatory role of NF-κB pathway ( Chen and Stark, 2019 ). For example, endogenous sulfur dioxide (SO 2 ) is found to play extensive regulatory roles in the cardiovascular system as a novel gasotransmitter ( Huang et al, 2016 ).…”

Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses

“…Accumulating evidence has illustrated that the nucleolus serves as a stress responsive organelle toward a variety of stresses including genotoxic stress, oxidative stress, heat shock, nutrient deprivations, virus infections, and oncogene activations [44,45,65]. These nucleolar stresses, as well as chemical or genetic interventions of ribosome biogenesis, are known to induce morphological and functional alterations in the nucleolus, which are coupled with the activation of p53 or other signaling pathways in a stimulus-and cell context-dependent manner [44,66]. This study uncovered that the metabolite acetyl-CoA can be a novel modulator of the nucleolus through protein acetylation.…”

Progress of clinical evaluation for vascular aging in humans

“…[56] Activation of the NF-κB pathway by nucleolar stress and induction of apoptosis by nucleolar sequestration of NF-κB/RelA may emerge as a mechanism of vascular aging. [57] Further studies are necessary for better understanding the relationship between the nucleolar homeostasis and the process of vascular aging.…”